Distal substitutions drive divergent DNA specificity among paralogous transcription factors through subdivision of conformational space
Year: 2015
Type: article
Abstract: Many genomes contain families of paralogs--proteins with divergent function that evolved from a common ancestral gene after a duplication event. To understand how paralogous transcription factors evolve divergent DNA specificities, we examined how the glucocorticoid receptor and its paralogs evolved to bind activating response elements [(+)GREs] and negative glucocorticoid response elements (nGREs). We show that binding to nGREs is a property of the glucocorticoid receptor (GR) DNA-binding domain (DBD) not shared by other members of the steroid receptor family. Using phylogenetic, structural, biochemical, and molecular dynamics techniques, we show that the ancestral DBD from which GR and its paralogs evolved was capable of binding both nGRE and (+)GRE sequences because of the ancestral DBD's ability to assume multiple DNA-bound conformations. Subsequent amino acid substitutions in duplicated daughter genes selectively restricted protein conformational space, causing this dual DNA-binding specificity to be selectively enhanced in the GR lineage and lost in all others. Key substitutions that determined the receptors' response element-binding specificity were far from the proteins' DNA-binding interface and interacted epistatically to change the DBD's function through DNA-induced allosteric mechanisms. These amino acid substitutions subdivided both the conformational and functional space of the ancestral DBD among the present-day receptors, allowing a paralogous family of transcription factors to control disparate transcriptional programs despite high sequence identity.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Funders: National Science Foundation, U.S. Department of Energy, W. M. Keck Foundation, American Heart Association, Emory University, Georgia State University, National Energy Research Scientific Computing Center, National Institutes of Health, Directorate for Computer and Information Science and Engineering, Office of Science, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, Division of Chemistry, Division of Molecular and Cellular Biosciences
Awards: G122673668, G1286236842, G1590157074, G1677143136, G1863003419, G2123841078, G239196684, CAREER: Modeling Assemblies and Interactions at the Replication Fork: Sliding Clamps and Clamp Loaders, G2740302234, Structural mechanism and function of endogenous ligands targeting orphan NR4A receptors, G2880384052, G3083819904, G3664434452, G382641700, G3892653051, G419881185, G42916606, G4501827968, G465867758, G498139845, G5076365615, G5094606986, G5233348002, G5510868622, G572720644, G5986892838, Integrative modeling of PCNA assemblies engaged in genome duplication and repair, G647246560, G6671297155, G6759286802, G7783184734, G9000107824, G9000279231, Graduate Training in the Pharmacological Sciences, G966696293, G969889393
OpenAlex ID: W2204493772